UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

Date: Jun e 18 ,20 14 OFFICE OF CHEMICAL SA F ET Y AND
POLLUTION PRE V ENTION

SUBJECT: Etridiaz ol e Human Hea l t h Ri s k Assessment Seeping Document in Support of Regis t ration Review

PC Code : 08470 1

Decision No.: 487058

Petition No .: NA

Risk Assessment Type: Single Chemical Aggregate

TXRNo.: NA

MRIDNo.: NA DP Barcode: D417573 Registration No .: NA Regulatory Act ion : Registration Re vi ew
Case No.: NA

CAS No. : 2593- 1 5-9

40 CF R : §180.370



### Danette Drew

, Chemist/Risk

# A;sc**~** - Ana Ri vera- Lupiariez, Chemi FROM:

William Irwin, Ph.D., DAB

, oxico l ogist 

## (A t**·~!)If** - -.......,. Seye d T adayon, Chem is

,.**~**

R isk Assessme n t Branches V a nd V II ../

### /V<..J(~.-O..A/\.JV

THROUGH: Mic h aelS. Metzge r, Branch Chief

, 

# {)J}.. YO------ Health Effects D iv ision (7509P)**·** 

## J

Ri s k Assessment Branches V and VI

# ~ Health Effects Division (7509P)

TO: Margaret Hathaway, Chemical R eview Manager

Pe sticide Re-Evaluation Division (7508P)

Office of Pesticide Pr ograms

Attached i s the Heal t h Effects Di vision's (HED) human health risk assessment see ping

document for etr idi azole to support the registration review process. HED ha s evaluated the status
of th e human health ri sk assessment for etridiazole to determine the scope of work necessary to
support registration review. The most r ecently completed human h ealt h ri sk assessment (for the

2000 Reregistration El igibility Decision, RED ) and updated toxicology and exposure data were considered as part of this seeping exercise.

Page 1 of2 5Executive Summary

HED has evaluated the available data and the most recent human health risk assessments for the fungicide etridiazole (5-ethoxy-3-trichloromethyl-1 ,2,4-thiadiazole), the active ingredient in enduse products such as Terr azole®, to determine the scope of work necessary to support the registration review process. HED has consic.lered the currently labeled use p atterns as well as the

available toxici ty and exposu re in formation. The most recent h uman health risk assessment for

etridiazole was completed on June 6, 2000 (D266264; HED Revised Risk Assessment for the Reregistration Eligibility Decision (RED) Document). The EPA RED was issued in September

2000.

E trid ia zo le is a fungicide registered for use on field cotton, turf (golf courses), nursery stock, and greenho use ornamentals. Etridiazole is also mixed with potting soil for commercial greenhouse

use and is used for tobacco float bed seedling treatments. 

### In addition, since th e September 2000

RED, Special Local Need (SLN) greenhouse us es on toma toes h ave been ap proved in AZ, CO,
FL, MN, MS, OK, PA, TN, and TX. The various seed treatment uses assessed for the 2000 RED

have r ece ntly been voluntarily cancelled by the registrant (79 FR 14247; 3/13/14).

The September 2000 RED identifi ed several outstanding toxicology data requirements, many of

them a r es ult of the original studies being unacceptable. Most of the required studies have since

been submitted (multi-generation reproduction st udy in rats, 1 -year chronic dog study, 28-day

inhalation study i n rats, 28-day dermal s tudy in rats, mouse carcinogenicity study, and a dermal penetration st udy) and are undergoing final review. Preliminary reviews indicate that th e
submitted studies are acceptable.

The acute neurotoxicity study (ACN), subchronic neurotoxicity study (SCN), and immunotoxicity study, now required in accordance with new data requirements for conventional pesticide regis tration (40 CFR Part 158 ), have not been submitted. The HED 's Ha za rd and

Science Policy Council (HASPOC) has determined, based on a weight of the evidence approach considering all t he available hazard and exposure inform ation for etridiazole, that the ACN,
SCN, and immunotoxicity studies can be waived. In addition, the HASPOC determined that the guideline requirement for a 90-day dog study can be waived (6/5/14 HASPOC meeting,
TXR#0053944). The toxicology database for etridiazole is complete.

The primary target for etrid iazol e toxicity is the liver, following chronic exposure in ra ts and dogs. A chronic population adjusted dose ( cP AD) was established based on the 2-year carcinogenicity study in rats ( liver and kidney effects). An acute populat ion adjusted dose (aPAD)

was determined for the population subgroup females 13-50 years, based o n s k e l eta l

malformations/variations observed in the rabbit fetuses that were presumed to occur after a sing le

exposure. Fo r short-term dermal and inha lat ion exposure and risk assessments, the rabbit developmental endpoint (oral study) was selected. For intermedi ate- and long-term dermal and

inhalation expos ure risk assessments, th e NOAEL was selected from the 2

- yea r carcinogenicity study in ra ts.

Page 2 of25Page 3 of 25

For chronic oral exposures, a 3x uncertainty factor was applied for the lack of an acceptable chronic study ; an additional 3x uncertainty factor was also applied to chronic oral exposures

because uncertainty existed due to the lack of an acceptable m ulti

- generation reproduction study

in rats.

Previously , in the 2000 RED, etridiazole was characterized as a mutagen. Some of the in vitro mutagenesis studies were positive at high c oncentrations ( greater than 121 μ M ) in mammalian

cells

. However, HED has reevaluated these data considering current science policies and

determined that e tridiazole should be considered non

- mutagenic because (1) mutagenicity occurred only at excessive doses relative to potential human doses, (2) some of the in vitro

mutagen icity studies in mammalian cells were n egative , even at higher doses of 323 μ M (near the solubility limit)

, and (3) the definitive in vivo mouse mutagenicity study was negative at doses up to 1000 mg/kg, approaching the oral LD 50 dose. Etridiazole is classified as a probab le

hu m an carcinogen based on the occurrence of m ultiple tu m or types in m ale and f e m ale rats. The

m ost potent unit risk Q 1 *, based on the thyroid f ollicular cell co m

bined adeno m as/carcino m as in

m ale rats, is 3.33 x 1 0

- 2 ( m g/kg/day)

- 1 in hu m an equivalents

.

The residue chemistry database for etridiazole is complete. The residues of concern for tolerance enforcement and risk assessment (plants and livestock) are etridiazole and its monoacid

metabolite ( 3

- carboxy

- 5

- ethoxy

- 1,2,4,

- thiadiazole ). The residue of concern for drinking water is parent etridiazole. Tolerances for residues of etridiazole and its monoacid metabolite in food and

feed commodities are established under 40 CFR 180.370. The tolerance for tomatoes will be re

evaluated based on residue data submitted since the RED for imported tomatoes

. The current tolerance expression should be updated to comply with HED’s current policy on tolerance expressions. There are currently no international maximum residue limits (MRLs) for etridiazole

so there are no harmonization issues with Codex, Canada, or Mex ico. The nomenclature and physiochemical properties of etridiazole can be found in A ttachment 1

.

There is a potential for non

- occupational post

- application dermal exposures for golfers playing

on etridiazole treated turf. While the golfer risk estimates were not of concern in the 2000 RED (assuming turf use mitigation s ), a n updated post

- application assessment for golfers on etridiazole

treated turf will be required under registration review since there have been significant changes in exposure assessment methodology ( updated 2012 R esidential SOP ) . Any revisions to toxicological PODs or uncertainty factors will be incorporated

. The chemical specific turf transferable residue ( TTR ) data used in the 2000 RED have since been determined to be unacceptable. Sinc e the estimated turf post

- application exposure using default TTR values for etridiazole is not minimal in comp arison to the level of concern ( i.e., the calculated MOE is not greater than 10 times higher than the level of concern ; MOE = 4 2 0 for females ages 13

- 49, compared to the LOC of 100), EPA is now requiring new TTR data for etridiazole

. The required

chemical

- specific TTR will also be considered in the post

- application assessment.

In the 2000 RED th ere were no acute or chronic aggregat e risk estimates (food and water) of

concern. The short

- term aggregate risk estimate (food and water plus golf course turf exposures)

was not of concern. T he cancer aggregate risk estimate (food and golf course turf exposures ) was not of concern assuming mitigations for turf use (restrict use to tees and greens only and reduce application rates). Drinking water was not aggregated in the cancer assessment as there was aPage 4 of 25

potential concern for estimated etridiazole concentrations in water alone

. It was determined upon issuance of the 2000 RED that potential cancer risks from drinking water would be mitigated by

the turf use restrictions.

Revised aggregate risk assessments may be performed for etridiazole if there are any signific ant changes to toxicological PODs or uncertainty factors, or if there are significant changes to dietary exposure estimates, or if there are significant changes to non

- occupational post

application exposures (based on the updated SOPs and on any new TTR da ta), or if EPA’s Environmental Fate and Effect Division (EFED) has determined that new estimated drinking water concentrations (EDWCs) are necessary

.

T here is the potential for short

- and intermediate

- term occupational exposure to etridiazole during handl ing ( dermal and inhalation exposures ) and post

- application (dermal exposures only)

activities for the current uses of etridiazole (cotton, nursery stock, turf, tobacco seedling, greenhouse ornamentals and greenhouse tomatoes)

. Occupational handler and p os t

- application

exposure assessments were performed for the 2000 RED for the current uses of etridiazole, except for the greenhouse tomato use , and no risks of concern were identified with mitigation

measures

.

U pdated quantitative handler and post

- application occupational risk assessment s will be performed for etridiazole to include updated exposure assessment methodology and any

revisions to toxicological PODs or uncertainty factors. An occupational risk assessment will be performed for the gr eenhouse tomato use. A new chemical specific handler exposure study for greenhouse use has been submitted and may be used in the handler assessments

. S ince the estimated occupational turf post

- application exposure using default TTR values for etridiazole i s not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern of 100), and existing TTR data for etridiazole are unacceptable, EPA is now requiring new chemical specific TTR data . Estimated screening level

dermal MOEs are 74 for shor t

- term and 28 for intermediate

- term exposures at the current Restricted Entry Interval (REI) of 12 hours. The required chemical specific TTR will also be considered for the post

- application assessment.

Hazard Identification/Toxicology

T he September 2000 etridiazole RED identified the following outstanding toxicology data requirements, many of them a result of the original studies being unacceptable: a repeat multi

generation reproduction study in rats (protocol to include early thyroid measurements), a repeat chronic toxicity study in dogs, a repeat carcinogenicity study in mice, a 28

- day inhalation toxicity study in rats

, and a 21

- day dermal study in rats.

Since the issuance of the 2000 RED, the fol lowing new toxicological data have been submitted: a

multi

- generation reproduction study in rats ( MRID 46057101), a 1

- year chronic dog study (MRID 45793201), a 28

- day inhalation study in rats (MRID 45812401), a 28

- day der mal study in rats (MRID 45714601), a mouse carcinogenicity study (MRID 46426701), and a dermal penetration study (MRID 45943701 ). Preliminary reviews indicate that the s ubmitted studies are acceptable.Page 5 of 25

The ACN and SCN studies and an immunotoxicity study are now required in accordance with new data requirements for conventional pesticide registration (40 CFR Part 158); these studies have not been submitted for etridiazole. The HED’s Hazard and Science Policy Council (HASPOC) determine d based on existing data and weight of the evidence, that the neurotoxicity ( ACN, SCN ) and immunotoxicity studies can be waived for etridiazole. The guideline requirement for a 90

- day non

- rodent study (i.e. 90

- day dog study ) has also been waived (6/5/14 HASPOC meeting; TXR #0053944 ). The toxicological database for etridiazole is now complete.

The pri m ary target for etridiazole toxicity is the liver, following chronic exposure in rats and dogs

. Syste m ic toxicities observed in the 2

- year rat carcinogenicity study include increased

absolute and relative liver weights, hepatocyto m egaly, spongiosis hepatis, clear, basophilic, and eosinophilic hepatocellular alterations, hepatic centrilobular pig m entation and cholangiectasis.

Additional toxicities observed in this study were decreased b ody weight gains, renal tubule cell karyo m egaly and testicular interstitial cell hyperplasia. In the two

- year chronic toxicity study in dogs, syste m ic toxicity in both sexes m anifested as increased serum aspartate a m inotransferase (SGOT) and serum alkaline phosphatase (ALK;SAP) activity, increased relative liver weights,

liver pathology consistent with cholestatic hepatitis, secondary bile nephrosis and increased pro

thro m bin ti m e.

The rat developmental study indicated decreased fetal weights and increased re sorptions, however at doses higher than the maternal LOAEL. The rabbit developmental study indicated decreased fetal body weights/viability and increased incidence of skeletal ma lformations, but at doses equal to the maternal LOAEL. There was no quantitative or qualitative evidence of

increased susceptibility in the f etuses or the offspring of rats or rabbits following pre

- and/or postnatal exposure to etridiazole. In the prenatal develop m ental toxicity studies in rats and

rabbits and the m ulti

- generation reproduction study in rats, any observed toxicity to the fetuses or off s pring occurred at equivalent or higher doses than did toxicity to parental ani m als. Although

the Hazard Identification Assessment Review Committee (HIARC) had deter m ined that the original m ulti

- generation reproduction study in rats was an unacceptable

- guideline study and not adequate for regulatory purposes, the study results suggest that the observed offspr ing effects (reduced pup weights) occurred only at a treat m ent level which resulted in parental toxicity (TXR # 0013543, 6/29/99)

. An acceptable reproduction study has since been submitted and it also indicates that any observed toxicity to the fetuses or offspring occurred at equivalent doses as parental animals

.

Although there is no indication of neurotoxicity in any of the m a mm alian toxicity studies

sub m itted for the 2000 RED

, m ost of these studies were determined to be ina dequate f or regulatory

purposes and it was determined that there were insufficient data to assess the neurotoxic potential

of etridiazole. However, the HASPOC has since recommended that the requirement for

neurotoxic ity studies be waived.

Etridiazole induced genotoxic responses in several in vitro m utagenicity assays whereas responses were negative in vivo

. Positive responses occurred in the gene m utation assay in the bacterial study in Salmonella typhimurium and in the in vitro sister chro m atid exchange assays in Chinese

ha m ster ovary cells at concentrations greater than 121 μM . However, the in vitro concentrationsPage 6 of 25

which caused positive responses in mammalian cells were high doses of 121

- 2 4 2 μM

, and t hese

blood le vels in vivo are unlikely to be produced during normal exposure scenarios

. Previously, in the 2000 RED, etridiazole was characterized as a mutagen

. However, HED has reevaluated these data considering current science policies and determined that etridiazole should be considered as

non

- mutagenic because (1) mutagenicity occurred only at excessive doses relative to potential human doses, (2) some of the in vitro mutagen icity studies in mammalian cells were negative

,

even at higher doses of 323 μM (near the solubility limit)

, and (3) the definitive in vivo mouse mutagenicity study was negative at doses up to 1000 mg/kg, approaching the oral LD 50 dose

.

Analysis of whole body eli m ination in m ale and fe m ale rats indicated that etridiazole is rapidly

absorbed and most eli m ination occurs within 48 hours of dosing. The m etabolite profile in urine

was si m ilar between sexes and a m ong the four dose groups; m etabolites were identified as etridiazole carboxylic acid, ethyl (a m i nocarbonyl) carba m ate, N

- carboxy oxa m i c acid and N

acetyl cysteinyl conjugate of etridiazole.

Etridiazole is classified as a Group B2 che m ical (probable hu m an carcinogen) based on the

occurrence of m ultiple tu m or types in m ale and f e m ale rats (tu m or sites noted were the liver, bile
duct, m a mm ary gland, thyroid, and testes), including the induction of a rare bile duct tu m or (cholangiocarcino m a). A linear, low

- dose approach (Q 1 *) is used for hu m an risk

characterization. The m ost potent unit risk Q 1 *, based on the thyroid f ollicular cell co m

bined

adeno m as/carcino m as in m ale rats, is 3.33 x 1 0

- 2 ( m g/kg/day)

- 1 in hu m an equivalents [converted

from ani m als to hu m ans by use of the ( m g/kg body weight) 3/4 interspecies scaling factor]. The original mouse cancer study was unacceptable , but it indicated the presence of gross and histopathological lesions in the lungs

, a concern for possible evidence of carcinogenicity in a different organ in a different species. However, an acceptable mouse cancer study did not report lung effects, but liver tumors were observed.

Etridiazole has a low order of acute toxicity via oral, der m al, or inhalation routes (Toxicity Category III or IV), produces m ild irr itation to the eyes (Toxicity Category III) and it is a skin

sensitizer.

In the 2000 etridiazole RED, a n FQPA uncertainty factor of 3x was recommended because of

the lack of an acceptable m ulti

- generation reproduction study in rats, which could identify potential reproductive effects to the parental ani m als or to the offspring following pre/post natal

exposure to etridiazole. Th at factor was reduced to 3x because: (i) there was no quantitative or qualitative indication of increased susceptibility in the prenatal d evelop m ental toxicity

studies in rats and rabbits (ii) although the m ulti

- generation reproduction study in rats was deter m ined to be an unacceptable

- guideline study and not adequate for regulatory purposes by

the HIARC (TXR # 0013543, 6/29/99)

, the study results suggest that the observed offspring

effects in this study occurred only at a treat m ent level which resulted in parental toxicity and (iii) adequate data were available or conservative m odeling assu m ptions are used to assess the potential for dietary (food and drinking water) exposure to infants and children. A multi

generation reproduction study has since been submitted and preliminary reviews indicate that the study is acceptable. T he FQPA safety factor determination will be revisited during registration review.Page 7 of 25

An acute population adjusted dose ( aPAD ) was not deter m ined for the general population

because an appropriate endpoint attributable to a single expo s ure (dose) was not identified

in oral toxicity studies. Therefore, an acute dietary risk assess m ent was not required for the general population.

However, an a PAD was deter m ined for the population sub group, fe m ales 13

- 50 years, based on skeletal m alfor m ations/variations ( m issing sternebrae and tail defects) observed in the rabbit

fetuses that were presu m ed to occur after a single exposure (dose). As per the reco mm endation of the FQPA Safety Factor Co mm ittee (6/3/99), the 3x uncertainty factor for the lack of a

multi

- generation reproduction study was not applied to the population subgroup

, females 13

- 50, for the estimation of acute dietary ris k . The Co mm ittee m ade this reco mm endation

because no increased susceptibility was seen following in utero exposure, and in addition, the

results of the m ulti

- generation reproduction study m ay not provide an endpoint of concern (i.e.,

an in utero effect) on the potential for adverse effects occurring after a single exposure (dose ). The total uncertainty factor for the acute assessment was 100 x ( 10x for intraspecies extrapolation and 10x for interspecies variation).

A chronic population dose ( c PAD ) was established based on the two

- year carcinogenicity study in

rats (liver and kidney effects) which included the application of an uncertainty factor of 300 (10x for intraspecies extrapolation, 10x for interspecies variation and a 3x applied under FIFRA for the lack of an acceptable chronic study)

. A s per the reco mm endation of the FQPA

Sa f ety Factor Co mm ittee (6/3/99), an additional 3x uncertainty factor was applied to the

chronic dietary risk assessment because uncertainty exist ed due to the lack of an acceptable

m ulti

- generation reproduction study in rats, which could identify potential toxicities following

exposure to etridiazole in the offspring and/or the parental ani m als. The total uncertainty factor

for the chronic assessment was 1000. The uncertainty factor determinations will be revisited during registration review.

The HIARC identified doses and endpoints for short

- , inter m ediate

- , and long

- term der m al and

inhalation exposures (TXR # 0013543, 6/29/99) . For short

- term der m al exposure and risk

assess m ents, the rabbit develop m ental NOAEL was selec t ed from the develop m ental toxicity study in rabbits. This dose and endpoint were selected because: 1) the develop m ental effect s are considered short

- term and thus are appropriate for this exposure period (i.e., 1

- 7 days) of

concern, 2) the reproductive/fetal para m eters are not evaluated in the der m al toxicity study and

thus the consequences of these effects cannot be ascertained for the der m al route of exposure

and 3) this endpoint will provide adequate protection for t h e subpopulation of fe m ales 13+ years old

, i.e., pregnant workers (the population subgroup showing the most sensitive point of departure is fe m ales of child

- bearing age [13

- 50 years old]). In addition, the two existing 21

- day der m al toxicity studies in rabbits were classified by the HIARC as unacceptable because of

m ajor deficiencies.

Since no inhalation studies were available (with the exception of an acute inhalation toxicity study) in the etridiazole data base, the oral deve l op m ental NOAEL was also selected for a short

term inhalation exposure (1 to 7 days) and risk assess m ent.Page 8 of 25

For inter m ediate

- and long

- term der m al and inhalation exposure risk assess m ents, the NOAEL

was selected from the two

- year carcinogenicity study in rats. The dosing time frame represented by this study best represents the intermediate

- term and chronic exposure durations considering the toxicity data available.

No der m al absorption study wa s available in the etridiazole toxicity data base for the previous

risk assessment. In addition, the der m al toxicity studies sub m itted to the Agency were evaluated

and deter m ined to be inadequate for regulatory purposes. Therefore, the default value of 100%

der m al absorption (relative to oral absorption ) was used in the 2000 risk assess m ent. Also, inhalation toxicity was assumed to be equivalent to oral toxicity

. An acceptable rat dermal absorption study has been submitted since the RED. Dermal absorption was 28.96%, 14.63%, 16.49% at 4 hours and 22.47%, 16.94%, and 16.62% at 10 hours at doses of 0.099, 0.975 and 10.25 μg/cm 2 , respectively. The new dermal and inhalation studies will be evaluated for use in

future etridiazole risk assessm ents.

See A ttachment 2 for a summary of the toxicological endpoints and points of departure (PODs)

used in the 2000 etridiazole risk assessment, available toxicity studies, and the toxicity profile.

Conclusion

The September 2000 etridiazole RED identified several toxicology data requirements, many of them a result of the original studies being unacceptable. Most of the required studies have been

submitted and have undergone preliminary review . The ACN, SCN, and immunotoxi ci ty studies

have no t been submitted. The HED’s Hazard and Science Policy Council (HASPOC ; 6/5/14;

TXR # 0053944 ) has determine that

, based on a weight of the evidence approach considering all the available hazard and exposure information

, the ACN, SCN

, immunotoxicity , and 90

- day dog studies may be waived for etridiazole. The toxicity database is complete for etridiazole. During registration review, the toxicological endpoint s , points of departure and uncertainty factors will

be re

- evaluated to consider the new data submissions and to comply with current HED policies.

Residue Chemistry and Dietary Exposure

Residue Chemistry

T he residue chemistry database for etridiazole is complete . The 6/2000 HED risk assessment had identified a requirement for storage stability data on the etridiazole monoacid metabolite (a residue of concern) in livestock commodities. Those data have not yet been submitted. Available

dat a indicate that a Categor y 3 situation ( 40 CFR 180.6(a)3 “ no reasonable expectation of finite

residues ”) exists with respect to residues of etridiazole and the monoacid metabolite in meat, mbyp (meat by

- products), fat, and milk of cattle, goats, hogs, horses, sheep, and in poultry

, poultry fat, mbyp, and eggs and there are currently no tolerances for etridiazole in livestock

commodities. HED has reexamined the storage stability data requirement and does not believe that the results of a storage stability study on the monoacid metab olite in livestock commodities will alter the 180.6(a)3 status since etridiazole residues are not expected to be found in any feed

items for livestock. The only livestock feed items with tolerances for etridiazole (after

cancel l ation of the seed treatment uses) are cottonseed and cotton gin byproducts. In field trialsPage 9 of 25

with exaggerated application rates (6x) to cotton

, parent etridiazole and the monoacid metabolite were not detected above the method limit of quantitation in cottonseed or cotton byproducts.

H ED is not requiring the additional storage stability data at this time and the previous requirement is now waived.

In the 2000 RED a dditional residue data were required for imported tomatoes. Since then, residue studies for tomatoes grown in Spain, Italy, the Netherlands, and the U.K. have been submitted (MRIDs 45939402 and 46407801 ) and will be evaluated under registration review for adequacy in meeting the data requirement. The current tolerance for tomatoes is based on residue

data that were submitted f or domestic use on tomatoes

. All other plant tolerances are based on the sum of the enforcement method limit of quantitation (LOQ) for etridiaz ole and its monoacid

metabolite as there were no detectable residues in the field trial studies. Most of the curr ent
etridiazole tolerances are based on the seed treatment uses which have recently been canceled (use on the seeds of barley, corn, peanut, safflower, sorghum, wheat, and legume vegetable crop groups 6 and 7). See Attachment 4 for a list of current U.S. t olerances.

The residues of concern for tolerance enforcement and risk assessment (plants and livestock) are etridiazole and its monoacid metabolite, 3

- carboxy

- 5

- ethoxy

- 1,2,4,

- thiadiazole . The residue of concern for drinking water is parent etridiazole. Existing a nalytical m ethods are considered adequate for both data collection and enforcement purposes.

Dietary Assessment

Food

Acute

, chronic

, and cancer dietary exposure analyses for etridiazole were performed using the Dietary Exposure Evaluation Mode l (DEEM ) for the 2000 RED (D.Drew, 11/29/99, Etridiazole (Terrazole)

- Revised Acute and Chronic (Cancer and Non

- Cancer) Dietary Exposure Analyses

. D261366). These assessments were for food only and did not include drinking water. Both

residues of concer n (etridiazole and the monoacid metabolite) were included. F or the acute and chronic analyses, tolerance residue levels and 100% percent crop treated (CT) were assumed. The acute dietary risk estimate of 3.6% of the aPAD did not exceed HED ’ s level of conc ern for

females 13

- 50 years (the only population subgroup which had an acute toxicity endpoint identified). The chronic dietary risk estimates did not exceed HED ’ s level of concern for the U.S. population and all subgroups. The most highly exposed populati on subgroup was children 1

- 6 years old at 31% of the cPAD . The cancer dietary exposure analysis was refined by using residue

levels of half the combined levels of quantitation ( LOQs ) for etridiazole and monoacid metabolite for all commodities except tomatoes (domestic tomato tolerance was used for imported tomato commodities) and weighted average %CT estimates (BEAD 6/ 15/ 99). The

cancer dietary risk estimate for etridiazole was 1.6 x 10

- 7 for the general U.S. population.

Water

The Environmental Fate and Effects Division (EFED) provided estimated drinking water concentrations (E DWCs ) of etridiazole in surface and groundwater for use in the 2000 RED drinking water assessment. E DWCs res ulting from turf (golf course) use were used in thePage 10 of 25

drinking water risk assessment as that scenario resulted in high

- end protective estimates ( Environmental Fate and Effects Division Risk Assessment for the Reregistration Eligibility

Decision on 5

- ethoxy

- 3

- trichloromethyl

- 1,2,4

- thiadiazole (Etridiazole), 5/22/00 and Terrazole: Refined Tier I Chronic Surface Water EECs for Use in the Human Health Drinking Water Risk

Assessment , 5/26/00). E DWCs included parent etridiazole only as it was determined that because of the low volume of etridiazole used on golf course turf and the relative stability of the parent compound to abiotic degradation, the metabolite is not expected to contribute significantly to drinking water risk.

For surface water, the GENEEC model was used to estimate acute and chronic concentrations resulting from the use on golf course tees, greens and fairways. Chronic E DWC s derived from GENEEC for turf use were refined with the incorporation of a percent crop area (PCA) factor of

17%. The surfa ce water E DWCs were compared to calculated Drinking Water Levels of

Co mparison (DWLOCs)

, i.e., levels remaining in the ‘risk cup’ after accounting for food exposures, and it was determined that there was no concern for etridiazole in drinking water for

ac ute and chronic exposures. However, potential concentrations of etridiazole in surface water for turf use (32.3 ppb), assuming treatment of tees, greens and fairways, were above the cancer DWLOC of 1 ppb for the general U.S. population. It was determined u pon issuance of the 2000 RED that potential cancer risks from drinking water would be mitigated by the removal of fairways from the etridiazole labels; applications to golf courses are limited to tees and greens only.

Ground water concentrations of etridi azole were estimated using the SCI

- GROW (Tier I)

computer model for use on golf course turf. Groundwater EDWCs were below the DWLOCs for all population subgroups for acute, chronic and cancers risks, and were not a concern.

Conclusion

There are adequate residue chemistry data. T he tolerance for tomatoes will be re

- evaluated based

on the residue data submitted (since the RED) for imported tomatoes. A new dietary assessment may be performed if 1) there are any significant changes to toxicological PODs or uncertainty factors, 2) EFED determine s that new EDWCs are necessary using updated models or PCA

factors , or 3) residue chemistry review results in recommendations for significantly higher

tomato t olerances than currently established

.

Non

- Occupational Exposure

There are currently no registered residential or homeowner uses for etridiazole ; however, as etridiazole can be applied to golf courses up to several times a year, there is a potential for non

occupational exposure to adults and children entering treated golf courses. Only dermal exposures are expected for post

- application exposures to treated golf courses.

Residential Handlers

A residential handler exposure assessment is not required because etridiazole is only applied to use sites that are not treated by residential handlers ; there are no homeowner uses.Page 11 of 25

Non

- Occupational Post

-

Appl ication

Etridiazole is restricted from use on residential turf and lawns ; however, etridiazole may be used

on golf course turf

. A dults and children may experience post

- application dermal exposure to
etridiazole as a result of golfing activities.

A post

- application golfer assessment ( short

- term and cancer) was performed for the 2000 RED

. Only females ( ages 13

- 49 years) were assessed for short

- term dermal exposures since an appropriate short

- term endpoint was not identified for the general population, including children. This assessment was performed utilizing a (now unacceptable) turf transferable residue (TTR) study specific for etridiazole. Th at MOE was estimated at 17,000 (the level of concern (LOC) is a MOE of less than 100).

L ifetime c an cer risk estimate s of 1.2 x 10

- 7 (2 days of exposure per year) and 1.3 x 10

- 6 (18 days exposure per year) were determined for all adult golfers using Agricultural Reentry Task Force ( ARTF ) data and assuming golf course turf mitigations of reduced application rates and restricting use to tees and greens only.

Since th e 2000 etridiazole assessment , the residential Standard Operating Procedures ( SOP s, 2012) ha ve been updated and several assumptions have changed. While a chemical

- specific TTR study is available f

or etridiazole (MRID 43287802; 1993) and was used in the 2000 assessment

, substantive data quality issues were identified during Agency review (D266856

, Bangs, G., 2000). Furthermore, the study does not meet current policy guidelines and is no longer considered acceptable for use in risk assessment. The measured transferable residues were mostly below the laboratory limit of quantitation (LOQ), which was inappropriately high; therefore only higher residues were detected and any finite residues below the LOQ were not measured. In addition, the study did not use the modified California roller method of collection so the measured residues may be an underestimate of expected transferable residues. Because of

the issues identified with this study , HED has at this time completed a screening level short

- term
risk estimate based on current default TTR values. The estimated short

- term dermal MOE for female golfers is 4 2 0

.

In accordance with the updated Part 158 d ata requirements (2007), a turf transferrable residue (TTR) study is required for all occupational or non

- occupational residential turf uses . Suitable TTR data are not available for etridiazole. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Proce dures for Residential Pesticide Exposure Assessment

, HED analyzed all of the available TTR data and selected new liquid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR ). This

defaul t is 0.2% for granular formulations. Of the available TTR studies submitted to the Agency,

the maximum F AR value seen using a granular product was 0.69% or 3.5 times higher than the default residue transfer value. Therefore, HED has decided that a calcul ated MOE of approximately 10 times higher than the LOC (e.g., an MOE >1,000 if the LOC = 100) using the default residue transfer values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific TTR study ( HE D Memo, 12/12/12, “ Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR)Page 12 of 25

Studies ” ). For the turf use of etridiazole, a TTR study will be required for r egistration r eview

since the available study is unacceptable and the estimated short

- term dermal MOE for golfers

are lower than 1000 using the current default values ( the screening MOE is 4 2 0 for female golfers, ages 1 3

- 49 )

.

Post

- A pplication Volatilization/Spray Drift

Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of etridiazole. The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policie s and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency's risk assessments. The need for spray drift and volatilization risk assessment for etridiazole will be examined during reg istration review

.

Conclusion

A n updated post

- application assessment for golfers on etridiazole treated turf will be performed under registration review since there have been significant changes in exposure assessment methodology (updated 2012 residential SOP). Any revisions to toxicological PODs or uncertainty factors will be incorporated

. The chemical specific TTR data used in the 2000 RED have since been determined to be unacceptable. Since the estimated turf post

- application exposure using default TTR values for etridiazole is not minimal in comp arison to the level of concern ( i.e., the calculated MOE is not greater than 10 times higher than the level of concern ; MOE = 4 2 0 for females ages 13

- 49, compared to the LOC of 100), EPA is now requiring new TTR data for etridiazole

. The required chemical specific turf transferable residue (TTR) will also be considered for the post

- application assessment.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), EPA must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential (non

- occupational) exposures. EPA has considered aggregate exposures for acute, chronic,

short

- term

, and lifetime cancer durations in its 2000 risk assessments ; those results are

summarized below

.

Acute and Chronic

Acute and chronic dietary risk estimates (food and water) were not of concern for any population subgroup.

Short

- term

T he short

- term risk estimate for combined dietary (food and water) and post

- application golf

course exposures was not of concern.

CancerPage 13 of 25

The cancer aggregate (food plus two golf course post

- application exposure s per year ; no water)

risk was estimated at 2.8 x 1 0

- 7 assuming the golf course use mitigations

. There was potential

cancer risk concern for estimated concentrations of etridiazole in surface water

- based drinking

water , so water exposures were not combined with the food and golf course exposures in the

cancer aggregate assessment

. It was determined upon issuance of the 2000 RED that potential cancer risks from drinking water would be mitigated by the removal of fairways from the

etridiazole labels ( applications to golf courses are limited to tees and greens only )

.

Conclusions

Revised aggregate risk assessments may be performed for etridiazole if there are any significant changes to toxicological PODs or uncertainty factors, if there are significant changes to dietary exposure estimates

, if there are significant changes to non

- occupati onal post

- application exposures (based on the updated SOPs and on any new TTR data) , or if EPA’s Environmental Fate and Effect Division (EFED) has determined that new estimated drinking water concentrations (EDWCs) are necessary

.

Occupational Exposure

Occupational uses of etridiazole include use on field cotton, turf (golf courses), nursery stock

, and greenhouse ornamentals

. Etridiazole is also mixed with potting soil for commercial greenhouse use and is used for tobacco float bed seedling treatments

. There are also greenhouse

uses on tomatoes that have been approved for various states ( Special L ocal Need , SLN ) since the

2000 RED. Greenhouse tomato worker scenarios have not yet been assessed. The seed treatment

uses assessed in the 2000 RED have been v oluntarily cancelled by the registrant. T here is the potential for short

- and intermediate

- term , as well as lifetime occupational exposure to etridiazole during handling (mixing, loading, and applying ; dermal and inhalation exposures ) and

post

- application activities (dermal exposures only )

. Etridiazole is applied by groundboom, automated irrigation systems (chemigation)

, mechanically pressurized handgun, or tractor

- drawn spreader

.

Occupational Handlers

The 2000 RED identified risks of concern for some occupational handler exposure scenarios (i.e ., seed treatments and turf applications); therefore, mitigation measures were implemented such as product use site restrictions, cancelled formulation types (i.e . dust and some granular products), reduced application rates, and requirement of additional PPE (e.g., respirator)

. R egistered etridiazole labels require occupational handlers to wear long

- sleeved shirts, long pants, shoes, socks, and chemical resistant g loves. Mixer/loaders must also wear a chemical resistant apron. Additionally, some labels require the use of protective eyewear and organic vapor (OV) filtering respirators during mixing and loading scenarios, due to the high vapor pressure (1.1 x 10

- 2 m m Hg) of etridiazole. In the RED, h andler risk was assessed using data from the Pesticide Handlers Exposure Database (PHED) Version 1.1

.Page 14 of 25

Although occupational handler assessment s have been conducted to estimate risk for all existing

uses of etridiazole (except for greenhouse tomato SLNs) , the assessment s w ere not conducted based on current occupational exposure policies

. Recommended unit exposures for occupational

handler assessments ha d generally been derived only from the Pesticide Handlers Exposure Database (PHED). However, recently both the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available, the Age ncy will continue to replace existing data. N ew exposure monitoring

data will be incorporated into revised occupational handler assessments , as necessary, during registration review.

S ome etridiazole labels have been amended after the RED. For example, to bacco float bed seedling uses are permitted for liquid formulations (EPA Reg. No. 400

- 422) ; previous

assessments were done only on the wettable powder and no risks of concern were identified

. Exposure from mixing and loading (M/L) liquid formulations is ex pected to be lower than exposure from M/L wettable powder . The assessment for mixing and loading wettable powder

formulations for tobacco float bed seedling scenarios is considered protective of potential

handler exposure s from mixing and loading of liquid formulation for this handler scenario.

A chemical specific handler exposure study “Dermal and Inhalation Potential Exposure to Greenhouse Handlers While Mixing, Loading, and Applying Terrazole 35% Wettable Powder” (MRID 45773201) was submitted after the issuance of the RED. The study was reviewed by HED (D286169, Crowley, M., 09/22/2011) and may be used in registration review to update occupational exposure assessments of soil drenching or watering

- type foliar applications in greenhouses using mechan ically

- powered handwands.

Occupational Post

-

Application

Post

- application exposure assessments have been performed (in the 2000 RED) for the current

uses of etridiazole , except for the greenhouse tomato use

, and no risks of concern were identified

with m itigations. Recommended transfer coefficients for occupational post

- application

assessments were derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer

coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data.

HED will incorporate new exposure monitoring data, as necessary, during registration review.

There is a possibility for workers to have post

- application dermal exposure to etridiazole treated

turf (i.e., golf course maintenance workers) . Based on the discussion in the non

- occupational

post

- application section

, a TTR study will be required for r egistration r eview since estimated dermal MOEs for occupational post

- application turf scenarios are lower than 10X the target LOC (i.e., MOEs of 1000). Using updated metho ds , s creening level estimated d ermal MOEs are below the target MOE of 1000 at 74 for short

- term and 2 8 for intermediate

– term exposures at the current Restricted Entry Interval (REI) of 12 hours

. Note that these screening MOEs ar e also

below the LOC of 100 at the current 12 hour REI.Page 15 of 25

A quantitative post

- application exposure assessment was not performed for transplanting

etridiazole

- treated tobacco seedlings (float beds). T he occupational handler assessment for this

tobacco seedl ing use is expected to be protective of potential post

- application exposure for workers transplanting the treated seedlings.

Conclusion

U pdated quantitative handler and post

- application occupational risk assessment s (cancer and

non

- cancer) will be performed to include updated exposure assessment methodology, and any

revisions to toxicological PODs or uncertainty factors. An occupational handler risk assessment should be performed for the greenhouse tomato use. The new chemical specific greenhouse

ha ndler exposure data may be considered for use in certain handler assessments. Also, s ince the

estimated occupational t urf post

- application exposure using default TTR values for etridiazole is not minimal in comparison to the level of concern (i.e., the ca lculated MOE is not greater than 10 times higher than the level of concern of 100 ), and existing TTR data for etridiazole are unacceptable, EPA is requiring new chemical specific TTR data. Estimated screening level

dermal MOEs are 74 for short

- term and 28 for intermediate

– term exposures at the current Restricted Entry Interval (REI) of 12 hours. The required chemical specific turf transferable residue (TTR) will also be considered for the post

- application assessment.

Public Health a nd Pesticide Epidemiology Data

HED has performed a recent review of human incident data for etridiazole (S. Recore, 2/4/14,
D417574, Terrazole: Tier I Review of Human Incidents ). Based on the low frequency and low severity of incident cases reported for etridiazole (IDS and SENSOR

- Pesticides), there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis

will be in cluded in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, the U.S. tolerance expression for etridiazole is expressed as “5

- ethoxy

- 3

- (trichloromethyl)

- 1,2,4

- thiadiazole and its monoacid metabolite 3

- carboxy

- 5

- ethoxy

- 1, 2,4

- thiadiazole ”. The correct definition should be :

Tolerances are established for residues of the fungicide etridiazole, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of etridiazole (5

- ethoxy

- 3

- trichloromethyl

- 1,2,4

- thiadiazole) and its monoacid metabolite (3

- carboxy

- 5

- ethoxy

- 1,2,4,

- thiadiazole), calculated as the stoichiometric equivalent of etridiazole, in or on the commodity.

There are currently no international maximum residue limits (MRLs) for etridiazole; therefore, there are no harmonization issues with Codex, Canada, or Mexico. See Attachment 4 for a table

of U.S. tolerances.

International or Intergo vernmental Work SharingPage 16 of 25

There is no current or forecasted work sharing efforts with other entities (e.g. California, Canada,
EU, and OECD ) for etridiazole.

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not identified etridiazole as part of a common mechanism group and a cumulative assessment has not been conducted.

Data Requirements

Toxicology

None.

Residue Chemistry

None.

ORE

Turf Transferable Residue (TTR) Study: There is a possibility for golfers and golf course maintenance workers to have post

- application dermal exposure to etridiazole treated turf. Based on the discussion in the non

- occuaptional and occupational post

- appl ication section s of this document

, a chemical specific TTR study will be required for etridiazole r egistration r eview since estimated dermal MOEs for turf post

application scenarios ( golfers and golf course maintenance workers) are lower than 10X the LOC ( screening level MOEs are <1000 and the LOC is 100 ).

Attachments

Attachment 1 . Chemical Identity

Attachment 2

. Doses and Toxicological Endpoints

Attachment 3. Toxicology Data Requirements and Toxicity Profiles

Attachment 4. U.S. and International To lerances and Maximum Residue LimitsPage 17 of 25

Attachment 1. Chemical Identity

Table A1.1. Etridiazole Nomenclature.

Compound

Common name Etridiazole

IUPAC name 5

- ethoxy

- 3

- (trichloromethyl)

- 1,2,4

- thiadiazole

CAS name 5

- ethoxy

- 3

- (trichloromethyl)

- 1,2,4

- thiadiazole

CAS registry number 2593

- 15

- 9

End

- use products (EP) Terrazole

Table A1.2. Physicochemical Properties of the Technical Grade of Etridiazole

Parameter Value Reference

Melting point 19.9 ° C a

Density 1.503 at 25 ° C a

Water solubility 100 ppm at 25° C b

Solvent solubility soluble in acetone, carbon tetrachloride, ethanol, ether, and xylene b

Vapor pressure 1.1 x 10

- 2 mm Hg at 25° C b

Dissociation constant, pK a pKa = 2.77 a

Octanol/water partition coefficient, Log(K OW ) 2.344 x 10 3 b

UV/visible absorption spectrum 288 nm a

a HSDB (Hazardous Substances Data B ank); http://toxnet.nlm.nih.gov

b D266264; HED Revised Risk Assessment for the Reregistration Eligibility Decision (RED) Document ; 6/6/2000.Page 18 of 25

Attachment 2. Doses and Toxicological Endpoints

Summary of Toxicological Doses and Endpoints used in Etridiazole Human Health Risk Assessment (2000)

.
Exposure/

Scenario POD Uncertainty/ FQPA Safety

Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General population including infants and children) An appropriate endpoint attributable to a single expo s ure (dose) w a s not identified in oral toxicity studies

(including the developmental toxicity s t udies in rats and rabbits) that is applicable to subpopulations other than

females of childbearing age (13

- 50 y ears old).

Acute Dietary (Females 13

- 49 years of age) NOAEL =

1 5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Acute Rfd =

0.1 5 mg/kg/day

aPAD =

0.1 5 mg/kg/day Rabbit Developmental Study

LOAEL = 45 mg/kg/day based on educed fetal body w e ights, decreased viability

and external and skeletal

malformations/variations in the rabb i t developmental toxicity stud y

.

Chronic Dietary (All Populations) LOAEL =

4. 8 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 3 X Chronic Rfd =

0.016 mg/kg/day

cPAD = 0.005 mg/kg/day Rat Chronic Study

LOAEL = 30.43 /38.45 mg/kg/day based

on increased absolute and relative liver

w eights, renal tubule cell kar y omegal y
, hepatoc y tomegaly and spongiosis hepatis

in the t w o

- y ear carcinogenicity study in

rats.

Dermal &

Inhalation:

Short

- Term (1

- 30 days) NOAEL =

15 mg/kg/day

Dermal Absorption

Factor of 100%

Assumed UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 Rabbit Developmental Study

LOAEL = 45 mg/kg/day based on educed fetal body w e ights, decreased viability

and external and skeletal

malformations/variations in the rabb i t developmental toxicity stud y

.

Dermal &

Inhalation

Intermediate

term (1

- 6 months) LOAEL =

4.8 mg/kg/day

Dermal Absorption

Factor of 100%

Assumed UF A = 10 X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 Rat Chronic Study

LOAEL = 30.43/38.45 mg/kg/day based

on increased absolute and relative liver

w eights, renal tubule cell kar y omegal y
, hepatoc y tomegaly and spongiosis hepatis

in the t w o

- y ear carcinogenicity study in

rats.

Dermal & Inhalation Long

term LOAEL =

4.8 mg/kg/day

Dermal Absorption

Factor of 100%

Assumed UF A = 10X

UF H = 10X FQPA SF = 3 X Residential LOC

for MOE = 3 00 Rat Chronic Study

LOAEL = 30.43/38.45 mg/kg/day based

on increased absolute and relative liver

w eights, renal tubule cell kar y omegal y
, hepatoc y tomegaly and spongiosis hepatis

in the t w o

- y ear carcinogenicity study in

rats. Cancer (oral, dermal, inhalation) Group B2 c h e mi ca l

- A Prob a ble hum a n c a r c i noge n

- Q* = 3.33 x 10 - 2 (mg/kg/ d a y ) - 1 in

human equivalents [converted from animals to humans by use of the (mg/kg body w e ight ) : cross species scaling factor]. Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- obs erved adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. HEC = human equivalent concentration.Page 19 of 25

Attach ment 3. Toxicology Data Requirements and Toxicity Profiles

3.1 Toxicology Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of etridiazole are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table 3.1 Toxicology Requirements for E tridiazole

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity

................................ ...................... 870.1200 Acute Dermal Toxicity

................................ ................. 870.1300 Acute Inhalation Toxicity

................................ ............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ ............. 870.2600 Dermal Sensitization

................................ .................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral Sub

- chronic (Rodent)

................................ ........... 870.3150 Oral Sub

- chronic (Non

- Rodent)

................................ ... 870.3200 21

- Day Dermal

................................ ............................. 870.3250 90

- Day Dermal

................................ ............................. 870.3465 90/28

- Day Inhalation

................................ .................... yes
yes
yes CR
CR yes

yes**

yes *

yes *

870.3700 Developmental Toxicity (Rodent)

............................... 870.3700 Developmental Toxicity (Non

- rodent)

......................... 870.3800 Reproduction

................................ ................................ yes
yes
yes yes

yes
yes *

870.4100 Chronic Toxicity (Rodent)

................................ ........... 870.4100 Chronic Toxicity (Non

- rodent)

................................ ..... 870.4200 Oncogenicity (Rat)

................................ ....................... 870.4200 Oncogenicity (Mouse)

................................ .................. 870.4300 Chronic/Oncogenicity

................................ .................. yes

no
yes
yes
yes yes

yes
yes
yes
yes

870.5100 Mutagenicity: Gene Mutation

- bacterial

...................... 870.5300 Mutagenicity: Gene Mutation

- mammalian

................. 870.5375 Mutagenicity: Structural Chromosomal Aberrations

.... 870.5395 Mutagenicity: Cytogenetics
870.5500 Mutagenicity: Other Genotoxic Effects

........................ yes
yes
yes
yes
yes yes

yes
yes
yes
yes

870.6100 Acute Delayed Neurotoxicity (Hen)

............................. 870.6100 90

- Day Neurotoxicity (Hen)

................................ ......... 870.6200 Acute Neurotoxicity Screening Battery (Rat)

............... 870.6200 90

- Day Neurotoxicity. Screening Battery (Rat)

........... 870.6300 Developmental Neurotoxicity

................................ ...... no

no
yes
yes CR yes

yes
yes +

yes +

yes

870.7485 General Metabolism

................................ ..................... 870.7600 Dermal Penetration

................................ ....................... 870.7800 Immunotoxicity....................................................................... yes

no

yes yes

yes

yes+

CR= conditionally required ; * Studies submitted and currently under review ; **Satisfied by the chronic dog study +Waived by HASPOC (meeting 6

- 5

- 14)Page 20 of 25

3.2 Toxicity Profiles

Acute Toxicity Profile for Etridiazole

Guideline MRID# Study T y p e * Resu lts Tox.

Cat. Classificatio n

870.1100 (§81

- 1) 43724501 Acute Oral

- Rat (2/8/94) L D 50 (males) = 1141 mg/kg

L D 50 (females) = 945 mg/kg

L D 50 (males and females combined) = 1028 mg/kg III Acceptable

Guideline

870.1200 (§81

- 2) 43724502 Acute Dermal

- Rabbit (2/8/94) L D 50 (males and females combined) > 5000 mg/kg IV Acceptable

Guideline

870.1300 (§81

- 3) 43724503 Acute Inhalation

- Rat (2/8/94) L C 50 (males and females combined) > 5.7 mg/L IV Acceptable

Guideline

870.2400 (§81

- 4) 43724504 Primary E y e Irritation

- Rabbit (2/8/94) Moderate E y e Irritant III Acceptable

Guideline

870.2500 (§81

- 5) 43724505 Primary Dermal

Irritation

– Rabbit (2/8/94) Non Irritant IV Acceptable

Guideline

870.2600 (§81

- 6) 43724506 Dermal Sensitization

- Guinea pig

- unspecified purity of terrazole technical (1/22/93) Moderate Dermal Sensitizer N/A Acceptable

Guideline

*The percent active ingredient of the technical test m aterial used in each of the acute toxicity studies was reported as 98.6% a.i.,

unless specified otherwisePage 21 of 25 Sub

- chronic and Chronic Toxicity Profile for Etridiazole

Guideline MRID# Study T y pe* R esults

870.3100 (82

- 1a) 00001700 90

- Day Oral T o xicity

- Rat, technical; 50% a.i. (1964) NOAEL (males, females) = 312 ppm LOAEL (males, females) = 625 ppm based on increased liver

to body w e ight ratios and gro w th depression

Classification: Unacceptable

- Guideline (not upgradable)

870.3150 (82

- 1b) 00001699 90

- Day Oral T o xicity

- Dog, technical; 50% a.i. (1964) NOAEL (males, females) > 1600 ppm LOAEL (males, females) = not established

Classification: Unacceptable

- Guideline (not upgradable)

870.3200 (82

- 2b) 00063303 21

- Day Dermal T o xicity

- Rabbit, unspecified purity (1/11/65) NOAEL (males, females) = not established LOAEL (males, females) = not established

Classification: Unacceptable

- Guideline (not upgradable)

870.3200 (82

- 2b) 00114197 21/28

- Day Dermal

T o xicity

- Rabbit,

T e rrachlor Super X

Formulation (6/65) NOAEL (males, females) = 0.65 ml/kg/day LOAEL (males, females) = 1.30 ml/kg/day based on increased kidney to body w e ight ratios

Classification: Unacceptable

- Guideline (not upgradable)

870.3200 (82

- 2b) 45714601 28

- Day Dermal Toxicity Study

- Rat (2002) Curr ently under review

870.3465 45812401 28

- Day Inhalation Toxicity Study

- Rats (2002) Currently under review

Chronic Tox i c ity

870.4100 (83

- 1b) 00001697 Chronic T o xicity

- Dog (8/5/68) NOAEL (males, females) = 2.5 mg/kg/day LOAEL (males, females) = 25 mg/kg/day based on increased

SGOT and SAP activit y , increased liver to body w e ight ratios, liver pathology consistent w ith cholestatic hepatis, secondary bile nephrosis and incre ased prothrombin time.

Classification: Acceptable

- Non GuidelinePage 22 of 25 870.4100 (83

- 1b) 45793201 Chronic T o xicity

- Dog (2002) NOAEL: 4.11/15.5 mg/kg/day (M/F)

LOAEL : 12.54 mg/kg bw/day in males, based upon increased alkaline phosphatase release and 37.4 8 mg/kg bw/day in females based upon increased ALP release and decreased body weight.

Classification: Acceptable

- Guideline

870.4200 (83

- 2a) 40747901 Oncogenicity

- Rat (6/23/88) NOAEL = 100 ppm (4.8/5.9 mg/kg/da y , males/females)

LOAEL = 640 ppm (30.43/38.45 mg/kg/da y
, males/females) based on decreased body w e ight gain (females), increased liver w e ight (absolute and relative), renal

tubule cell kar y omegaly (males, females), hepatoc y tomegaly (males), spongiosis hepatis (males), cholangiectasis (females)

and centrilobular pigmentation (females).

Etridiazole has carcinogenic potential in the livers of female rats, and the testes and t hy roid of male rats. It can also induce cholangiocarcinoma, a rare tumor, predominantly in

female rats.

Classif ication: Acceptable

- Guideline

870.4200 (83

- 2b) 00093744 Oncogenicity

- Mouse (3/14/81) NOAEL (males, females) = 640 ppm (91 mg/kg/da y ) LOAEL = 1280 ppm (183 mg/kg/da y ) based on minor decreases in body w e ight and food efficienc y , stomach h y perkeratosis, nephritis and adrenal and ovarian degeneration in females, lung h y perplasia in males, and spleen alterations in both sexes

Under conditions of this stud y , there w a s equivocal

evidence of carcinogenicity based on an increased

incidence of alveologenic carcinoma female mice.

Classification: Unacceptable

- Guideline (not upgradable)

870.4200 (83

- 2b) 46429701 Oncogenicity

- Mouse (2004) NOAEL = 50 ppm (males 7.5/females 9.1 mg/kg/day).

LOAEL = 1300 ppm (males 185/females 222 mg/kg/day), based on increased mortality (both sexes), increased liver weight (both sexes), which correlated with an increased incidence of enlarged livers, decreased kidney weight (both sexes), increased incidence of extramedullary hematopoiesis in the spleen (both s exes), degenerative and regenerative lesions in the liver (both sexes), liver tumors, heart lesions (mineralization of myofiber and thrombus), and kidney infarcts.

At the high

- dose level [2000/1600 ppm, (males 263/females 312 mg/kg/day)], increased mort ality and incidence of clinical signs, decreased body weight/body

- weight gain in males, increased spleen weight (males), and an increased incidence of liver tumors were

observed.

Classification: Acceptable

- Guideline

D e v e lopment a l/R e producti v e Tox i c ityPage 23 of 25

870.3700 (83

- 3a) 00120415 Developmental T o xicity

- Rat (5/27/82) Maternal T ox icity NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day based on clinical signs of toxicity (anogenital matting) Developmental T o xicity NOAEL = 30 mg/kg/day

LOAEL = 75 mg/kg/day based on decreased fetal body

w e ights and increased late resorptions

Classification: Acceptable

- Guideline

870.3700 (83

- 3b) 00104999 Developmental T o xicity

- Rabbit (5/22/79) Maternal T ox icity NOAEL = 15 mg/kg/day LOAEL = 45 mg/kg/day based on increased mortality and decreased body w e ights Developmental T o xicity NOAEL = 15 mg/kg/day LOAEL = 45 mg/kg/day based on reduced fetal body w e ights, viability and increa s ed incidence of external and skeletal

malformations/variations

Classificati on: Acceptable

- Guideline

870.3800 (83

- 4) 00001698 Multi

- generation

Reproductive T o xicity

- Rat (1968) S y stemic/Parental/Offspring T ox icity

NOAEL = 80 ppm (4 mg/kg/da y )

LOAEL = 640 ppm (32 mg/kg/da y ) based on reduced body w e ights of adult animals and pups Reproductive T o xicity NOAEL $ 640 ppm (32 mg/kg/da y ) LOAEL > 640 ppm (32 mg/ k g/da y ), not established

Classification: Unacceptable

- Guideline (not upgradabl e )

870.3800 (83

- 4) 46057901 Multi

- generation Reproductive T o xicity

- Rat (2003) Currently under review

Mutagenicity

870.5100 (84

- 2) 00093742 Gene Mutation in

Salmonella typhimurium and

Escherichia coli (11/2/81) Negati v e. Etridiazole did not induce a mutagenic or genotoxic effect under any test condition in any assa y

.

Classification: Unacceptable

- Guideline (not upgradable)

870.5100 (84

- 2) 00073206 Gene Mutation in

Salmonella typhimurium (10/77) Positi v e

. Etridiazole induced a mutagenic response in Salmonella typhimurium strain T A100 at non

- c y totoxic doses of 0.02, 0.06 and 0.2 Fg/plate

- S9 activation. T here w a s, ho w ever, no evidence of a mutagenic effect in the presence of S9

activation. Etridiazole w a s not mutagenic in strain T A98.

Classification: Acceptable

- Non

- guidelinePage 24 of 25 870.5300 (84

- 2) 00093743 Gene Mutation/ In vitro mammalian cell assay in Chinese hamster ovary

cells (11/10/81) Negati v e. Etridiazole did not induce a mutagenic effect in Chinese hamster ovary cells at non

- c y totoxic concentrations of

0.001

- 0.008% (equivalent to 10

- 80

μ g/mL)

- S9 activation and 0.001

- 0.005% (equivalent to

10

- 50 μ g/mL) +S9 activation after a 16 or 5 hour incubation period, respectivel y

.

Classification: Acceptable

- Guideline

870.5385 (84

- 2) 41837501 C y togenetics/ In vivo

mouse micronucleus

assay (10/30/85) Negati v e. T here w a s no evidence of either a clastogenic or aneugenic effect in male and female mice administered 1000 mg/kg etridiazole at any sacrifice time at a dose near the oral

LD 50 dose

.

Classification: Acceptable

- Guideline
870.5900 (84

- 2) 00120414 Other Mutagenic

Mechanisms/ In vitro

Sister Chromatid Exchange in Chinese hamster ovary cells (1/26/81) Positi v e

. Etridiazole induced increases in the frequency

of sister chromatid exchanges per cell at concentrations of

0.002 to 0.005% (equivalent to 20 to 50 μ g/mL)

- S9 activation and 0.002 and 0.003% (equivalent to 20 and 30

μ g/mL) +S9 activation after a 27.5 or 4 hour incubation period, respectivel y

. Note that the S9 treatment is cytotoxic after 6 hours of exposure, so the 4 hour data is more appropriate.

Classification: Acceptable

- Guideline 870.5375/

870.5900 (84

- 2) 00120416 Other Mutagenic

Mechanisms/ In vitro

C y togenetics/ Sister Chromatid Exchange in Chinese hamster ovary cells (6/4/82) Positi v e

. Etridiazole induced increases in the frequency

of sister chromatid exchanges per cell at concentrations of

0.003

- 0.005% (equivalent to 10

- 50 μ g/mL)

- S9 after a 27

- 28 hour incubation period. In addition, etridiazole induced increases in the frequency of c ells w ith structural chromosomal

aberrations at concentrations of 0.005% and 0.006% (equivalent to 50 and 60 μ g/mL)

- S9 activation an d
0.003, 0. 005 and 0.006% ( equivalent to 30, 50 and

6 0 μ g/mL) +S9 activation after a 6 or 2 hour incubation period, respectivel y

.

Classification: Acceptable

- Guideline

Metabolism

870.7485 (85

- 1) 43654801 Metabolism

- Rat (4/28/95) Etridiazole is rapidly absorbed and most elimination

occurs w ithin 48 hours of dos i ng. T he metabolite profile in

urine w a s similar bet w een s e xes and among the four dose groups; metabolites w e re i dentified as etridiazole carbox y lic acid, eth y l ( a minocarbon y l) carbamate, N

- carboxy oxamic acid

and N

- a c et y l c y stein y l conjugate of etridiazole.

Classification: Acceptable

- Guideline

870.7600 45943701 In vivo dermal absorption The dermal absorption study indicated it had 28.96%, 14.63%, 16.49% absorption at 4 hours and 22.47%, 16.94%, and 16.62% at 10 hours at doses of 0.099, 0.975 and 10.25 μg/cm 2

, respectively.

Classification: Acceptable

- GuidelinePage 25 of 25

Attachment 4: U

. S

. and International Tolerances and Maximum Residue Limits for

Etridiazole (PC Code 084701; 01/06/14)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex

40 CFR 180.370

(a) General : 5

- ethoxy

- 3

- (trichloromethyl)

- 1,2,4

- thiadiazole and its monoacid

metabolite 3

- carboxy

- 5

- ethoxy

- 1,2,4

- thiadiazole . None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex

Barley, grain * 0.1 Barley, hay * 0.1 Corn, field, forage * 0.1 Corn, field, grain * 0.1
Corn, field, stover * 0.1 Corn, sweet, forage * 0.1
Corn, sweet, stover * 0.1 Cotton, gin byproducts 0.1
Cotton, undelinted seed 0.1

Peanut * 0.1 Peanut, hay * 0.1
Safflower, seed * 0.1 Sorghum, grain, forage * 0.1 Sorghum, grain, grain * 0.1

Tomato 0.15 Vegetable, foliage of legume, group

7 * 0.1

Vegetable, legume, group 6 * 0.1 Wheat, forage * 0.1 Wheat, grain * 0.1
Wheat, straw * 0.1

Completed by: M. Negussie; 01/08/2014

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. *These commodity tolerances are associated with the cancel l ed seed treatment uses.